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系統識別號 U0026-1004201415355900
論文名稱(中文) 探討肺癌中甲型烯醇酶在免疫調控以及腫瘤轉移所扮演的角色
論文名稱(英文) Study on the Role of alpha Enolase in Immunomodulation and Tumor Metastasis in Lung Cancer
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 102
學期 2
出版年 103
研究生(中文) 蕭冠中
研究生(英文) Kuan-Chung Hsiao
電子信箱 randolph.hsiao@gmail.com
學號 TB8981057
學位類別 博士
語文別 英文
論文頁數 97頁
口試委員 指導教授-劉柯俊
口試委員-黃智興
口試委員-施能耀
口試委員-郭余民
口試委員-郭靜娟
口試委員-楊沂淵
中文關鍵字 肺癌  甲型烯醇酶  免疫抑制  轉移 
英文關鍵字 Lung cancer  ENO1  immunosuppression  metastasis 
學科別分類
中文摘要 我們先前之研究發現,腫瘤相關抗原甲型烯醇酶在非小細胞肺癌病患之腫瘤中有著高度的表現。同時研究數據顯示,腫瘤表現甲型烯醇酶較高量的病患,以及血中抗甲型烯醇酶抗體濃度較低的病患,其預後較差。因此,我們假設腫瘤可以藉由其高量表現的甲型烯醇酶對患者體內抗甲型烯醇酶的免疫反應進行調控,進而影響體內抗甲型烯醇酶抗體的產生。因此我們定期收集肺癌患者治療前後檢體,以探討其腫瘤存在與否,以及甲型烯醇酶的含量,與病患血中抗甲型烯醇酶抗體濃度之高低及免疫調控的關係。實驗結果顯示,大部分的病患在經由手術移除腫瘤後,其血中抗甲型烯醇酶抗體濃度,和術前相比均有上升的趨勢;同時大部分的病患在經由手術移除腫瘤後,其血中調節性T細胞的含量和術前相比有下降的現象。在追蹤達兩年的病患中,其術後一個月血中抗甲型烯醇酶抗體濃度和術前相比,變化量的中位數為12%。統計結果顯示治療後血中抗甲型烯醇酶抗體濃度增加未達12%者,預後較差。以高量表達甲型烯醇酶且具有將其表現在細胞表面特性的腫瘤細胞為材料進行動物實驗,結果顯示腫瘤可利用細胞表面所表現的甲型烯醇酶吸附抗甲型烯醇酶抗體,或是藉由分泌至細胞外的甲型烯醇酶和抗甲型烯醇酶抗體形成免疫複合體,進而降低血液中抗甲型烯醇酶抗體的濃度。當表達高量甲型烯醇酶之腫瘤在甲型烯醇酶或是卵清蛋白免疫過的小鼠體內生長時,小鼠體內會產生甲型烯醇酶特異性免疫抑制,而不會產生卵清蛋白特異性免疫抑制。在淋巴球增生試驗中,從腫瘤中分離出的調節性T細胞,明顯的抑制由甲型烯醇酶誘發的淋巴球增生,對卵清蛋白誘發的淋巴球增生抑制較弱。從以上結果我們知道在宿主中,表達高量甲型烯醇酶之腫瘤會誘發宿主產生甲型烯醇酶特異性免疫抑制。
除了在腫瘤中有高度表現外,我們也觀察到甲型烯醇酶在非小細胞肺癌腫瘤中,有表達在細胞表面的特性。在先前的研究中指出,甲型烯醇酶可表現在致病菌,以及活化的免疫細胞表面,以作為纖維蛋白溶酶原的受體,並參與瓦解細胞外間質,以達到全身性感染,或是移行到發炎組織的目的。因此我們假設腫瘤表面的甲型烯醇酶會與纖維蛋白溶酶原、尿激酶型纖維蛋白溶酶原激活因子及其受體結合,參與瓦解細胞外間質的過程並促進腫瘤轉移。由免疫螢光染色,以及墨點雜合法得知,甲型烯醇酶與纖維蛋白溶酶原、尿激酶型纖維蛋白溶酶原激活因子及其受體在細胞表面會有共同的分布位置並可相互結合。在體外實驗中,我們發現在細胞培養基中加入抗甲型烯醇酶抗體或是藉由RNA干擾技術抑制細胞甲型烯醇酶的作用或表現可減低胞外蛋白分解以及細胞外基質層侵襲的效率。在動物實驗中我們觀察到持續給予小鼠抗甲型烯醇酶抗體可以有效減緩腫瘤細胞產生肺臟轉移以及骨頭轉移的時間。從以上結果我們得知藉由抗甲型烯醇酶抗體阻斷甲型烯醇酶與其他蛋白交互作用,可以降低腫瘤細胞對胞外蛋白分解以及瓦解細胞外間質的能力,進而抑制腫瘤細胞遠端轉移的形成。
總結來說,我們發現高表達甲型烯醇酶的腫瘤細胞在生長時會抑制患者體內針對甲型烯醇酶所產生的免疫反應,進而減少抗甲型烯醇酶抗體的產生;並利用腫瘤細胞表面所表現的甲型烯醇酶作為纖維蛋白溶酶原的受體,和其他蛋白共同作用後對細胞外間質進行分解,以達到腫瘤生長以及轉移的目標。因此,激活患者體內抗甲型烯醇酶的免疫反應,將會有助於降低腫瘤細胞轉移的形成。
英文摘要 Our previous study has demonstrated that α-enolase (ENO1) is highly expressed in non-small-cell lung carcinoma (NSCLC). We also have found that patients with tumor expressing a higher level of ENO1 had a poorer prognosis. In another study, we have described that the serum level of anti-ENO1 antibody (Ab) in late-stage NSCLC patients was lower than that in early-stage NSCLC patients. Therefore, we hypothesized that tumor-derived ENO1 may suppress the anti-ENO1 immune response in cancer patients. In this study, we demonstrated that the serum level of anti-ENO1 Ab was increased, but the number of regulator T cells was decreased in most of patients after surgical treatment to remove tumor. We evaluated the correlation for the increment of anti-ENO1 Ab one month after surgery with the clinical outcome of patients who were followed up to two years by using the median of the increment of anti-ENO1 Ab one month after surgery (12%) as cutoff value. The poor prognosis in <12% increment of anti-ENO1 Ab group was observed. In animal studies, the mice were implanted with different numbers of tumor cells to allow formation of tumor masses of different sizes. After anti-mouse ENO1 monoclonal Ab (mENO1 Ab) was adoptively transferred, the clearance of mENO1 Ab was fast in mice with large tumor burden. In naïve mice, the clearance of mENO1 Ab was fast in mice with recombinant mENO1 administration. The mENO1-specific immune response in the mENO1-immunized mice was suppressed after implantation of tumor cells expressing high level of mENO1 by reducing the production of anti-mENO1 antibody and this suppression was not observed in ovalbumin (OVA)-immunized mice. Tumor-associated regulatory T cells suppressed the mENO1-induced proliferation of splenocytes derived from mENO1-immunized mice more substantially than OVA-induced proliferation of splenocytes derived from OVA-immunized mice in splenocytes proliferation assay. These results suggest that tumor-derived ENO1 may lead to induce an Ag specific immunosuppression and contribute to tumor progression.
Besides the overexpression of ENO1 in NSCLC cells, we also observed that ENO1 was displayed on the surface of NSCLC cells. ENO1 has been demonstrated to act as a plasminogen receptor on cell surface and participate in tissue invasion of pathogens and activated immune cells, which provided a possibility that surface-expressed ENO1 in tumor cell may be participated in extra cellular matrix (ECM) degradation and tumor metastasis. In dot blotting and proximity ligation assay, we demonstrated that ENO1 directly interacted with plasminogen (PLG), urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR). Treatment with an anti-ENO1 Ab or shRNA specific against ENO1 in vitro reduced the cell invasion by suppressed the ECM degradation. In animal study, adoptive transfer of mENO1 Ab delayed the establishment of tumor lung and bone metastasis. These results suggest that ENO1 on the surface of tumor cells participates in tissue invasion and tumor metastasis. Therefore, blocking surface-expressed ENO1 with specific Ab to inhibit or prevent tumor metastasis will be a therapeutic approach in lung cancer patients.
Taken together, we showed that tumor cells, with high level of expression of ENO1, induce an ENO1-specific immunosuppression in host to reduce the production of anti-ENO1 Ab during the period of tumor growth, and promote the ECM degradation by interacting of surface-expressed ENO1 with plasminogen and other proteins to establish a distant organ metastasis. Therefore, to arouse the anti-ENO1 immune response in cancer patients is a potent therapeutic approach to suppress tumor metastasis in the future.
論文目次 中文摘要 1
Abstract 3
Acknowledgement 5
List of Tables 7
List of Figures 8
List of Appendixes 10
Introduction 11
Objectives and experimental designs 18
Material and methods 19
Results 34
Discussion 46
Conclusion 56
References 57
Tables 69
Figures 71
Appendixes 95
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